Some radionuclides, atomic species that may exhibit radioactivity, are useful for diagnostic and therapeutic techniques such as tumor imaging and radiotherapy of tumors. The adoption and expanded use of these techniques has increased the demand for available supplies of carrier-free radionuclides having useful half-lives and suitable gamma and/or beta emission properties. Two radionuclides which have received particular attention for these purposes are technetium-99m (.sup.99m Tc, half-life 6.02 hours) used for diagnostic purposes and rhenium-188 (.sup.188 Re, half-life 16.98 hours) used for therapeutic and diagnostic purposes.
Technetium-99m (.sup.99m Tc) has been widely studied and used in diagnostic nuclear medicine since the later 1950s. .sup.99m Tc produces a readily imageable gamma emission (140 kev, 90%) which facilitates monitoring of its biodistribution when injected in vivo after conjugation or complex formation with other compounds, such as target-specific antibodies. The chemistry of technetium has been well developed, primarily through study of the relatively stable isotope technetium-99 (.sup.99 Tc, half-life 210,000 years).
Although the chemical properties of rhenium are not as well known as those of technetium, certain isotopes of rhenium exhibit properties that indicate it is suited for both radiodiagnostic and radiotherapeutic applications, for example, as a label for conjugation to monoclonal antibodies for targeting to tumors. .sup.188 Re (half-life 16.98 hours) has a longer half-life than .sup.99m Tc (6.02 hours), possesses a strong particulate emission (beta energy of 2.12 MeV, as compared with .sup.99m Tc which has no particulate emission), and has an imageable gamma emission (15%, 155 kev) suitable for gamma camera imaging of tumors. .sup.188 Re is derived from either natural rhenium-187 (.sup.187 Re) by neutron bombardment in a nuclear reactor or, preferably, from a .sup.188 W/.sup.188 Re generator made of a target tungsten material, enriched in W-186, by double neutron capture using a high-flux reactor. The nuclear properties of this isotopic system are as follows: ##STR1##
One method of producing .sup.99m Tc and .sup.188 Re involves extraction of a relatively short-lived "daughter" radionuclide as a decay product of a longer lived ("parent") radionuclide. For example, .sup.99m Tc is the daughter radionuclide of molybdenum-99 (.sup.99 Mo, half-life 66.02 hrs) and .sup.188 Re is the daughter of tungsten-188 (.sup.188 W, half-life 69.4 days). Devices known as generators have been commercially available to provide the parent radionuclide in convenient, ready-to-use form and to provide for separation of the daughter radionuclide from its parent radionuclide to obtain a supply of the relatively short-lived daughter isotope. The parent and daughter radionuclides may be separated using chromatographic, solvent extraction, or sublimation generators. Chromatographic generators, due to their simplicity and compact nature, are more convenient to use in hospitals and other institutions where radionuclides are used for diagnosis and therapy. For use in such generators, the parent radionuclide must have a sufficiently long half-life to provide for transit and storage prior to commencing the extraction procedure.
In one form of chromatographic generator, such as those used to produce .sup.99m Tc from .sup.99 Mo, insolubilized parent radionuclide is adsorbed onto a bed or column of material such as aluminum oxide ("alumina") for which the daughter radionuclide has relatively little affinity. The daughter radionuclide, which results from decay of the parent, is then periodically eluted from the column, for example, using physiological saline. Typically, the daughter radionuclide product will be of high specific activity and is referred to as "carrier free" since it is produced by beta decay of a parent radionuclide, and the product is relatively free of stable isotopes of the daughter radionuclide.
Although adsorption column chromatographic generators are capable of producing daughter radionuclides, chromatographic generators of this type are only able to provide high specific activity daughter radionuclides at relatively low concentrations from low specific activity (n,.gamma.) parent radionuclides, such as .sup.99 Mo and .sup.188 W, due to the necessity of using large quantities of alumina or other adsorption bed material and eluting solution to obtain the daughter radionuclide. As a result, fission- or high flux neutron capture-produced parent radionuclides were formely preferred for producing radionuclides such as .sup.99m Tc and .sup.188 Re. Unfortunately, fission-produced radionuclides require complex facilities and safety precautions that entail high costs relative to the amount of daughter radionuclide produced. In addition, the relatively short half-lives of the desired radionuclides, .sup.99m Tc and .sup.188 Re, preclude convenient production of fission- or neutron capture-produced radionuclides at an established nuclear reactor and subsequent shipment to a hospital or clinic for further preparation and use.
Recently, an alternative chromatographic .sup.99 Mo/.sup.99m Tc generator was developed, as described in Evans et al., U.S. Pat. No. 4,280,053, in which the parent isotope, .sup.99 Mo, is formulated directly into the solid phase of the generator column in the form of insoluble zirconium molybdate. In order to produce the Evans et al. .sup.99 Mo/.sup.99m Tc generator, molybdenum trioxide (enriched in .sup.98 Mo to produce .sup.99 Mo) is irradiated and then dissolved in a basic ammonia or sodium hydroxide solution. The resulting solution is acidified and added to an aqueous zirconium nitrate or zirconium chloride solution to obtain a zirconium molybdate precipitate in the form of a gel-like matrix. The matrix is then separated from the solution by filtration or evaporation, air dried and sized for use in the generator. The zirconium molybdate matrix is said to be non-elutable while allowing the daughter .sup.99m Tc in the form of pertechnetate ion, .sup.99m TcO.sub.4.sup.-,to freely diffuse from the matrix during elution. Since the parent .sup.99 Mo is incorporated directly into the gel, and is not retained by adsorption, the Evans et al. zirconium molybdate generator provides a significantly more dense .sup.99 Mo medium than prior alumina adsorption column generators.
More recently, U.S. Pat. No. 4,859,931, of Ehrhardt discloses an improved .sup.188 Re generator in which an insoluble zirconyl tungstate matrix containing .sup.188 W decays over time producing .sup.188 Re in the form of perrhenate (.sup.188 ReO.sub.4.sup.-), which is readily elutable from the matrix. The zirconyl tungstate matrix as disclosed in the Ehrhardt patent is produced by dissolving irradiated tungsten trioxide in a heated basic solution, adding the basic tungsten trioxide solution to an acidic zirconium-containing solution to obtain an acidic zirconyl tungstate slurry containing .sup.188 W, drying the slurry to form a permeable matrix, and then packing the matrix in an elutable column. The Ehrhardt generator has been found to be a highly effective generator of .sup.188 Re.
Although both the zirconyl molybdate generator system of Evans et al. and the zirconyl tungstate generator system of Enrhardt have proven to be effective for the production of .sup.99m Tc and .sup.188 Re, respectively, these systems have inherent drawbacks which limit their large-scale use and acceptability. Both systems require significant handling and processing of irradiated materials, including dissolution, precipitation, filtration, drying, gel fragmentation and column packing steps, all occurring after irradiation of the molybdenum trioxide or tungsten trioxide starting materials. These processing steps with irradiated materials necessitate the use of cumbersome shielded processing equipment, result in relatively high manufacturing costs and pose significant potential safety risks.
In order to overcome some of the foregoing problems in connection with the production of .sup.99m Tc, Narasimhan et al., "A New Method for .sup.99m Tc Generator Preparation," J. Radioanal. Nucl. Chem., Letters, Vol. 85, No. 6, pp. 345-356 discloses an improved method of preparing a zirconium molybdate .sup.99m Tc generator in which the precipitation, filtration, drying and fragmentation of radioactive materials required in the preparation of zirconium molybdate .sup.99m Tc generator are avoided by directly irradiating zirconium molybdate instead of molybdenum trioxide as disclosed by Evans. However, the direct irradiation of zirconium molybdate as reported by Narasimhan resulted in the production of radioactive contaminants unacceptable for clinical therapeutic or diagnostic applications, including .sup.97 Zr, .sup.95 Zr, .sup.175 Hf, .sup.181 Hf, and .sup.24 Na.